Abstract Incidence rates of Alzheimer's disease (AD) are expected to double from 1995 to 2050 creating a devastating global burden. Findings across individual studies regarding the effects of estrogen hormone therapy (E/HT) on cognition in postmenopausal women are inconsistent, likely as the result of methodological differences. Based on the accumulation of outcomes across numerous studies, several authors have postulated a "critical period" or "window of opportunity" when E/HT administration affords neuroprotection. The differential effects on cognition in younger versus older postmenopausal women is substantiated by combined evidence from animal and human studies. In addition, recent reanalysis of Women's Health Initiative (WHI) data found possible cardiac benefits with E/HT, but only in younger postmenopausal women. Regardless, since the initial release of the WHI negative findings, many women who might benefit from E/HT fear its use. Consequently, translational research models are needed to assist in parceling out the variables that confound the effects of E/HT on cognition in order to determine the best treatment practices for at risk populations. PUBLIC HEALTH RELEVANCE: Findings across numerous studies provide evidence that estrogen hormone therapy (E/HT) may be neuroprotective for at least some women when used in perimenopause or early menopause, but not in late menopause. Translational research models are needed to elucidate this "window of opportunity" in order to determine best treatment practices and populations who may or may not benefit from estrogen therapy. Given the rise in Alzheimer's disease prevalence, development of treatment protocols that could prevent or slow down disease progression are imperative.